Oral Presentation 35th Lorne Cancer Conference 2023

Inhibition of the npy signalling axis as a novel therapeutic option in pancreatic cancer. (#43)

Cecilia Chambers 1 , David Herrmann 1 , Peter Schofield 1 , Jessie Zhu 1 , Daniel Reed 1 , Victoria Lee 1 , Kendelle Murphy 1 , Michael Trpceski 1 , Lea Abdulkhalek 1 , Xanthe Metcalf 1 , Pauline Melenec 1 , Claire Vennin 1 , Max Nobis 1 , Marija Dinevska 2 , Sean Warren 1 , Sunny Wu 1 , Lei Zhang 1 , Ronaldo Enriquez 1 , Yanchuan Shi 1 , Mark Pinese 1 , Theo Mantamadiotis 2 , Nic Waddell 3 , Marina Pajic 1 , Owen Sansom 4 , Jennifer Morton 4 , Daniel Christ 1 , Herbert Herzog 1 , Paul Timpson 1
  1. The Garvan Institute of Medical Research, Sydney, NSW, Australia
  2. The Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria
  3. QIMR Berghofer Medical Research Institute, Herston
  4. Cancer Research UK Beatson Institute, Glasgow, United Kingdom

Due to surgically unresectable, locally advanced, or metastatic disease being present at the time of clinical diagnosis, pancreatic cancer (PC) is one of the most lethal forms of human cancer worldwide, with > 90% of patient deaths occurring within 1 year of diagnosis. Consequently, the development of more effective strategies to overcome these limitations and efficiently treat PC is required.

Previous research from the Garvan Institute has identified that Neuropeptide Y (NPY), normally produced by sympathetic neurons, has a strong cancer-promoting ability and inhibition of the NPY signalling axis in mouse models of Lewis Lung Carcinoma and B16F10 Melanoma significantly decreased tumour burden.

Using Q-RT-PCR, RNAscope and IHC we show that NPY was significantly upregulated in tumours from PC mouse models (FLOX, KPC) relative to wild-type pancreas. This evidence alongside NPY’s known role in numerous tumour-promoting pathways including cell proliferation1, tissue fibrosis2, angiogenesis3, and neuromodulation4 of the immune system led us to investigate further the role it plays in PC tumorigenesis.

Using pharmacological approaches to inhibit the NPY signalling axis, including a novel NPY-blocking antibody 5E12 created at the Garvan Institute (of which we also have a humanised version), we show that NPY and Y1R inhibition in a subcutaneous model significantly reduces PC tumour growth in combination with standard-of-care gemcitabine. Furthermore, in an intrasplenic model of PC metastasis, we show that combination of 5E12 and gemcitabine significantly reduces metastatic burden within the liver, which is the common site of metastasis in human patients. Additional anchorage-independent growth (AIG) assays that mimic the loss of ECM attachment suggest that the reduced metastasis upon NPY inhibition may be due to exposing PC cell vulnerability to chemotherapy while in transit to secondary sites.

Importantly, NPY inhibition in a long-term orthotopic setting significantly extended survival, and timepoint analysis of these tumours saw a significant reduction in CD31 positive cells suggesting an anti-angiogenic effect of inhibiting NPY. Finally, in a patient-derived xenograft exhibiting high NPY expression we saw a significant reduction in tumour growth upon NPY inhibition, thereby providing clinical relevance and feasibility for this project.

  1. Medeiros, P. J. et al. Neuropeptide y stimulates proliferation and migration in the 4T1 breast cancer cell line. International Journal of Cancer 131, 276–286 (2012)
  2. Dietrich, P. et al. Molecular cross-talk between Y5-receptor and neuropeptide Y drives liver cancer. Journal of Clinical Investigation (2020) doi:10.1172/jci131919.
  3. Chakroborty, D. et al. Neuropeptide Y, a paracrine factor secreted by cancer cells, is an independent regulator of angiogenesis in colon cancer. British Journal of Cancer 2022 127:8 127, 1440–1449 (2022).
  4. Wheway, J. et al. A fundamental bimodal role for neuropeptide Y1 receptor in the immune system. Journal of Experimental Medicine 202, 1527–1538 (2005).